Safety and Efficacy Study of Oral Fosfomycin Versus Oral Levofloxacin to Treat Complicated Urinary Syndromes (FOCUS)

This is a Phase 4, multi-center, open-label, randomized pragmatic superiority clinical trial
comparing two strategies for initial or step-down oral therapy for complicated urinary tract
infections (cUTI) without bacteremia with a uropathogen after 0-48 hours of parenteral
antibiotic therapy. The trial will evaluate the success and safety of a strategy of initial
or step-down fosfomycin, administered at a dose of 3 g once daily, vs. a strategy of initial
or step-down levofloxacin administered at a dose of 750 mg once daily. Investigator-directed
adjustment to another adequate oral therapy is allowed 1) if the causative pathogen is not
susceptible in vitro to quinolone initial or step-down therapy in a subject randomized to the
levofloxacin strategy, OR 2) if the subject develops a significant related AE (either grade 3
or at the investigator's discretion) to the initial or step-down oral therapy. The duration
of oral therapy (initial + subsequent if indicated) in each strategy is 5-7 days of any per
protocol antibiotic to which the pathogen is susceptible. The dosing of oral therapy depends
on creatinine clearance (CrCl). The trial will enroll approximately 634 patients that are
either male or female aged 18 or older with cUTI from outpatient and inpatient settings. The
study will take place over 25 months in approximately 12 to 15 US sites. The primary
objective is to compare Strategy 1 and Strategy 2 in terms of treatment success rates at Test
of Cure (TOC). The secondary objectives are: 1) to assess the safety of Fosfomycin; 2) to
compare Strategy 1 and Strategy 2 in terms of solicited adverse events; 3) to compare
Strategy 1 and Strategy 2 in terms of treatment success rates at End of Therapy (EOT).

Inclusion Criteria:

1. Have documented clinical signs and/or symptoms of complicated urinary tract infection
(cUTI) at diagnosis.

*Clinical signs and symptoms of cUTI include either:

1. Pyelonephritis, as indicated by at least 2 of the following:

- Documented fever (temperature greater than 38 degrees celsius) accompanied
by symptoms of rigors, chills, or "warmth"

- Flank pain

- Costovertebral angle tenderness on physical exam

- Nausea or vomiting

- Dysuria, urinary frequency, or urinary urgency OR

2. Complicated lower UTI, as indicated by at least 2 of the following new or
worsening symptoms of cUTI:

- Dysuria, urinary frequency, or urinary urgency

- Documented fever (temperature greater than 38 degrees celsius) accompanied
by symptoms of rigors, chills, or "warmth"

- Documented hypothermia (temperature less than 35.5 degrees celsius)

- Suprapubic pain or pelvic pain

- Suprapubic tenderness on physical exam

- New onset of foul smell to urine or increased cloudiness of urine per
subject or their caregiver

- Nausea or vomiting

AND at least 1 of the following complicating factors:

- Males with documented history of urinary retention

- Indwelling urinary catheter that is planned to be removed or replaced during
study therapy and before End of Therapy (EOT)

- Current obstructive uropathy that is scheduled to be medically or surgically
relieved during study therapy and before End of Therapy (EOT)

- Any functional or anatomical abnormality of the urogenital tract (including
anatomic malformations or neurogenic bladder) with voiding disturbance resulting
in at least 100 mL of residual urine

2. Able to understand and provide written informed consent. **A legally acceptable
representative may provide consent if the subject is unable to do so, provided this is
approved by local institution-specific guidelines.

3. Anticipated to be able to be stepped down or initially started on oral antibiotic
therapy within 48 hours of enrollment.

***The readiness of a subject for initial or step-down oral therapy is determined by
the primary medical team. In addition, For step down therapy the following conditions
have to be met: temperature at randomization must be less than 38C without any
rigors/chills AND the subject must have an improvement in baseline symptoms of cUTI
and no new cUTI symptoms.

4. Male or non-pregnant female.

5. Aged 18 years or older.

6. Women of childbearing potentia must agree to use an effective method of contraception
for the duration of the trial.

- Female is considered of childbearing potential unless postmenopausal, or
surgically/non surgically sterilized and at least 3 months has passed since
sterilization procedure. A woman is considered postmenopausal if her last
menstrual period was greater than or equal to 12 months.

- Includes, but is not limited to, non-male sexual relationships, abstinence from
sexual intercourse with a male partner, monogamous relationship with vasectomized
partner who has been vasectomized for greater than or equal to 180 days before
the subject receiving the first dose of study drug, barrier methods such as
condoms or diaphragms with spermicide or foam, effective intrauterine devices,
NuvaRing, and licensed hormonal methods such as implants, injectables but not
oral contraceptives.

7. If female of childbearing potential, a negative urine or serum pregnancy test within
48 hours of randomization.

8. Have pyuria (WBC count greater than or equal to 10/µL in unspun urine or greater than
or equal to 10 per high power field in spun urine) or dipstick analysis positive
(excluding "trace") for leukocyte esterase.

9. Have a pretreatment baseline urine culture specimen obtained within 48 hours before
the first dose of any antibiotic is administered (including pre-study antibiotics)

******Subjects may be enrolled in the trial and start study drug before the
investigator knows the results of the baseline urine culture.

10. Able to reliably take, tolerate, and absorb oral medications, at the investigator's
discretion.

11. Ability to understand study procedures and willing and able to comply with all
required procedures and visits for the duration of the trial.

Exclusion Criteria:

1. Have a documented history of any moderate or severe hypersensitivity or allergic
reaction to fosfomycin or a fluoroquinolone.

2. Have a concomitant infection at the time of randomization, which requires non-study
systemic antibacterial therapy effective against complicated Urinary Tract Infection
(cUTI) in addition to study drug.

3. Have received more than 48 hours of a potentially therapeutic antibiotic for treatment
of the current cUTI within 72 hours before enrollment.

*******Except if the following apply:

1. The subject has a known baseline urinary pathogen (urine culture positive) and
has failed prior therapy clinically (persistence of inclusion criteria) AND

2. The pathogen is known to be non-susceptible to the previous therapeutic regimen
used or the urine culture remains positive with a density of greater than or
equal to 105 CFU/mL

4. Women breastfeeding or donating breast milk.

5. Have intractable UTI infection at baseline that the investigator anticipates would
require more than 7 days of study drug therapy.

6. Have complete, permanent obstruction of the urinary tract.

7. Have confirmed fungal UTI at time of randomization (with greater than or equal to 103
fungal CFU/mL).

8. Have suspected or confirmed perinephric or intrarenal abscess.

9. Have suspected or confirmed prostatitis, epididymitis.

10. Have an ileal loop or known vesico-ureteral reflux.

11. Have a current urinary catheter that is not scheduled to be replaced before End of
Treatment (EOT).

*******Intermittent straight catheterization or replacement of new nephrostomy
catheters is acceptable.

12. Have planned inpatient urological intervention(s) for suspected infected kidney stone
or any other planned urological procedure with anticipated antibiotic prophylaxis
between randomization and End of Treatment (EOT).

13. Have bacteremia with a uropathogen causing cUTI.

14. Have an estimated or calculated Creatinine Clearance (CrCl) less than or equal to 20
mL/min or currently receiving hemo- or peritoneal dialysis at screening.

15. Have any condition or circumstance that, in the opinion of the investigator, would
compromise the safety of the subject or the quality of study data.

********Including any rapidly progressing disease or immediately life-threatening
(acute hepatic failure, respiratory failure or septic shock).

16. Have participated in any interventional trial of an investigational product within 30
days before the proposed first day of study drug administration.

17. Plans to participate or currently enrolled in any interventional study of an
investigational agent for the duration of the trial.

18. Previous randomization in this trial.

19. Any recent (less than 4 weeks) history of trauma to the pelvis or urinary tract.

20. Prior fosfomycin use in the past 12 months.